Field of the Invention
This invention relates to therapeutic agents and more particularly, to stabilized pharmaceutical compositions, preparations and formulations containing levothyroxine sodium, the sodium salt of the levo isomer of thyroxine, an active physiological thyroid hormone obtained from the thyroid gland of domesticated animals or prepared synthetically. Clinically, levothyroxine sodium serves as specific replacement therapy for reduced or absent thyroid function of any etiology, including human ailments such as myxedema, cretinism and obesity, in non-exclusive particular. The levothyroxine sodium is normally expressed chemically as C.sub.15 H.sub.10 I.sub.4 NaO.sub.4.XH.sub.2 O.
It is well known that the stability of the levothyroxine sodium hormone is quite poor, since it is hygroscopic and degrades rapidly under conditions of high humidity or in the presence of other moisture sources or light and under conditions of high temperature, especially in the presence of other pharmaceutical excipients such as carbohydrates, including lactose, sucrose, dextrose and starch, as well as certain dyes. Accordingly, commercially available levothyroxine sodium tablet preparations exhibit a very short shelf life, particularly as a unit dose, blister pack product. Occasional recalls of such tablet products have been ordered by the FDA due to tablet subpotency within the product expiration date. Due to this inherent instability, tablet formulations of levothyroxine sodium tend to degrade rapidly, particularly under conditions of high humidity and temperature.
It is therefore desirable to provide stable formulations of levothyroxine sodium tablets and capsules which may be employed in the treatment of human thyroid hormone deficiency conditions. This objective is achieved in a first embodiment by mixing a commercial grade of levothyroxine sodium with polyvinylpyrrolidone, also known as "PVP" or "Povidone USP", in the form of Plasdon C-15, K-29-32, K-90 (trademarks) or K-120 or Kolloidon 12 PF or 17 PF (trademarks) and at least partially dissolving the resulting mixture in a polar organic solvent such as water, methanol, ethanol, propanol, isopropyl alcohol, methylene dichloride or butanol, or a combination of these solvents, and adding a cellulose carrier component such as microcrystalline cellulose to the solution or mixture. The solvent component or components of the solution or mixture are removed by drying and the resulting fine powder is identified as a stable complex of levothyroxine sodium and polyvinylpyrrolidone dispersed on the surface of the cellulose carrier component. In an alternative embodiment the levothyroxine sodium is mixed with a Poloxamer such as Pluronic F-68 or Pluronic F-127, (trademarks) and the mixture is dissolved in one or more of the solvents identified above. The microcrystalline cellulose or alternative cellulose carrier component is then added, the resulting solution or mixture is dried to remove the solvent or solvents and the fine powder product is characterized by a stable complex of levothyroxine sodium and Poloxamer adsorbed on the cellulose carrier.
In a third embodiment, the levothyroxine sodium is at least partially dissolved in a polar organic solvent or solvents without the polyvinylpyrrolidone or Poloxamer and the cellulose carrier agent is added, after which the solvent is removed to leave the levothyroxine product adsorbed on the cellulose carrier.
The desired stabilized levothyroxine sodium dosage ingredient may also be prepared in a dry state by mixing commercially available levothyroxine sodium with a cellulose complexing agent such as low substituted hydroxypropyl cellulose by geometric dilution and subsequently combining this mixture with a cellulose carrier such as microcrystalline cellulose.
Various dry dosage formulations containing levothyroxine sodium, as well as processes of manufacture, are known in the art. U.S. Pat. No. 2,889,363, issued Jun. 2, 1959, to Ginger, et al and U.S. Pat. No. 2,889,364, dated Jun. 2, 1959, also to Ginger, et al, detail processes for producing thyroxine sodium. One of the problems facing manufacturers of such formulations is uniformly mixing the levothyroxine sodium with other inactive excipients to achieve a satisfactory "content uniformity" of the active levothyroxine sodium in the formulation matrix. Conventional powder mixing technology is not normally sufficiently refined to achieve a satisfactory uniform mix under these circumstances, particularly since the dose amount of levothyroxine sodium is very small, usually ranging from about 25 micrograms to about 300 micrograms per tablet dosage formulation. Since the ratio of active levothyroxine sodium to inactive excipients in the tablet matrix ranges from about 1 to 450 to about 1 to 5400, the problem of uniform mixing can be easily realized.
It is therefore an object of this invention to provide a stabilized formulation of levothyroxin sodium which resists degredation by light, heat, humidity or association with commonly used excipients.
Another object of this invention is to provide a stabilized dosage formulation complex of levothyroxine sodium and a selected Poloxamer.
Still another object of this invention is to provide a stabilized dosage formulation complex of levothyroxine sodium and polyvinylpyrrolidone.
A still further object of this invention is to provide a stabilized complex of levothyroxine sodium and a Poloxamer or polyvinylpyrrolidone adsorbed on a cellulose carrier, which stabilized complex is capable of being mixed with suitable excipients and compressed into tablets or placed in capsules as dosage structures characterized by uniform distribution of levothyroxine sodium in the tablet matrix or capsule.
Yet another object of the invention is to provide a stabilized complex of levothyroxine sodium adsorbed on a selected cellulose compound, either by dry mixing the levothyroxine and cellulose component or at least partially dissolving the levothyroxine and cellulose components in a polar organic solvent and removing the solvent.
Another object of this invention is to provide a process for producing a stabilized dosage formulation containing levothyroxine sodium by dry mixing levothyroxine sodium with polyvinylpyrrolidone or a suitable Poloxamer, dissolving the dry mixture in a polar organic solvent, adding a cellulose substance to the resulting solution and drying the solution or mixture to produce a fine powder characterized by a stabilized levothyroxine sodium-Poloxamer or levothyroxine sodium-polyvinylpyrrolidone complex uniformly dispersed on the cellulose carrier.
Yet another object of this invention is to provide a method for producing stabilized levothyroxine sodium dosage formulations which are suitable for mixing with various pharmaceutically acceptable excipients and compression into tablets or filling capsules, which method includes the steps of dry mixing commercial grade levothyroxine sodium having water of hydration with a suitable Poloxamer or polyvinylpyrrolidone powder, dissolving the dry mixture in a polar organic solvent which includes water, methanol, ethanol, propanol, isopropyl alcohol, methylene dichloride or butanol or a combination of these solvents, adding a cellulose carrier compound such as microcrystalline cellulose to the solution or mixture and heating the solution or mixture to evaporate the solvent or solvents and produce a fine levothyroxine sodium and Poloxamer or levothyroxine sodium and polyvinylpyrrolidone powder uniformly adsorbed on the microcrystalline cellulose.